The α1-adrenoreceptor antagonist-doxazosin (CARDURA®) has been safely used for the treatment of benign prostatic hyperplasia (BPH)1. It relaxes prostate smooth muscle through the blockade of α1-adrenergic innervation to the prostate. In addition, this alpha-blocker also exhibits moderate potency in inducing apoptosis in prostate cancer cells2-5, and shows synergistic antitumor effects in conjunction with radiation6 or certain chemotherapeutics such as adriamycin and etoposide7 against prostate cancer cells. In light of its potential use in the prevention/treatment of prostate cancer, the mechanism by which doxazosin mediates apoptosis has been the focus of many recent publications8.
It is noteworthy that the in vitro antitumor activity of doxazosin was suggested to be mediated by an α1-adrenoreceptor-independent pathway9. Putative mechanisms underlying doxazosin-mediated apoptosis include the upregulation of transforming growth factor-β (TGF-β) signaling and increased gene expression of p21 and IκBα (inhibitor of NF-κB α)10,11. However, the apoptotic mode of action of these compounds remains unknown.
Nevertheless, from a drug discovery perspective, separation of the effect of doxazosin on apoptosis in prostate cancer cells from its original pharmacological activity in normal cells suggested that a novel class of apoptosis-inducing agents could be created through lead optimization. The present invention thus presents this novel class of apoptosis-inducing agents.